10,10-dialkyl prostanoic acid derivatives as agents for lowering intraocular pressure

ABSTRACT

The present invention provides a method of treating ocular hypertension or glaucoma which comprises administering to an animal having ocular hypertension or glaucoma therapeutically effective amount of a compound represented by the general formula I;  
                 
 
     wherein the dashed line indicates the presence or absence of a bond, the hatched wedge indicates the α (down) configuration, and the solid triangle indicates the β (up) configuration;  
     B is a single, double, or triple covalent bond;  
     n is 0-6;  
     X is CH 2 , S or O;  
     Y is any pharmaceutically acceptable salt of CO 2 H, or CO 2 R, CONR 2 , NHCH 2 CH 2 OH, N(CH 2 CH 2 OH) 2 , CH 2 OR, P(O)(OR) 2 , CONRSO 2 R, SONR 2 , or  
                 
 
     R is H, C 1-6  alkyl or C 2-6  alkenyl;  
     R 2  and R 3  are C 1-6  linear alkyl which may be the same or different, and may be bonded to each other such that they form a ring incorporating the carbon to which they are commonly attached;  
     R 4  is hydrogen, R, C(═O)R, or any group that is easily removed under physiological conditions such that R 4  is effectively hydrogen;  
     R 5  is hydrogen or R;  
     R 6  is  
     iv) hydrogen;  
     v) a linear or branched hydrocarbon containing between 1 and 8 carbon atoms, which may contain one or more double or triple bonds, or oxygen or halogen derivatives of said hydrocarbon, wherein 1-3 carbon or hydrogen atoms may be substituted by O or a halogen; or  
     vi) aryloxy, heteroaryloxy, C 3-8  cycloalkyloxy, C 3-8  cycloalkyl, C 6-10  aryl or C 3-10  heteroaryl, wherein one or more carbons is substituted with N, O, or S; and which may contain one or more substituents selected from the group consisting of halogen, trihalomethyl, cyano, nitro, amino, hydroxy, C 6-10  aryl, C 3-10  heteroaryl, aryloxy, heteroaryloxy, C 1-6  alkyl, OR, SR, and SO 2 R.  
     Some of the compounds of the present invention and some of their methods of preparation are also novel an nonobvious.

FIELD OF THE INVENTION

[0001] The present invention relates to prostanoic acid derivatives aspotent ocular hypotensives that are particularly suited for themanagement of glaucoma.

BACKGROUND OF THE INVENTION

[0002] Description of Related Art

[0003] Ocular hypotensive agents are useful in the treatment of a numberof various ocular hypertensive conditions, such as post-surgical andpost-laser trabeculectomy ocular hypertensive episodes, glaucoma, and aspresurgical adjuncts.

[0004] Glaucoma is a disease of the eye characterized by increasedintraocular pressure. On the basis of its etiology, glaucoma has beenclassified as primary or secondary. For example, primary glaucoma inadults (congenital glaucoma) may be either open-angle or acute orchronic angle-closure. Secondary glaucoma results from pre-existingocular diseases such as uveitis, intraocular tumor or an enlargedcataract.

[0005] The underlying causes of primary glaucoma are not yet known. Theincreased intraocular tension is due to the obstruction of aqueous humoroutflow. In chronic open-angle glaucoma, the anterior chamber and itsanatomic structures appear normal, but drainage of the aqueous humor isimpeded. In acute or chronic angle-closure glaucoma, the anteriorchamber is shallow, the filtration angle is narrowed, and the iris mayobstruct the trabecular meshwork at the entrance of the canal ofSchlemm. Dilation of the pupil may push the root of the iris forwardagainst the angle, and may produce pupilary block and thus precipitatean acute attack. Eyes with narrow anterior chamber angles arepredisposed to acute angle-closure glaucoma attacks of various degreesof severity.

[0006] Secondary glaucoma is caused by any interference with the flow ofaqueous humor from the posterior chamber into the anterior chamber andsubsequently, into the canal of Schlemm. Inflammatory disease of theanterior segment may prevent aqueous escape by causing completeposterior synechia in iris bombe, and may plug the drainage channel withexudates. Other common causes are intraocular tumors, enlargedcataracts, central retinal vein occlusion, trauma to the eye, operativeprocedures and intraocular hemorrhage.

[0007] Considering all types together, glaucoma occurs in about 2% ofall persons over the age of 40 and may be asymptotic for years beforeprogressing to rapid loss of vision. In cases where surgery is notindicated, topical b-adrenoreceptor antagonists have traditionally beenthe drugs of choice for treating glaucoma.

[0008] Certain eicosanoids and their derivatives have been reported topossess ocular hypotensive activity, and have been recommended for usein glaucoma management. Eicosanoids and derivatives include numerousbiologically important compounds such as prostaglandins and theirderivatives. Prostaglandins can be described as derivatives ofprostanoic acid which have the following structural formula:

[0009] Various types of prostaglandins are known, depending on thestructure and substituents carried on the alicyclic ring of theprostanoic acid skeleton. Further classification is based on the numberof unsaturated bonds in the side chain indicated by numerical subscriptsafter the generic type of prostaglandin [e.g. prostaglandin E₁ (PGE₁),prostaglandin E₂ (PGE₂)], and on the configuration of the substituentson the alicyclic ring indicated by α or β [e.g. prostaglandin F_(2α)(PGF_(2β))].

[0010] Prostaglandins were earlier regarded as potent ocularhypertensives, however, evidence accumulated in the last decade showsthat some prostaglandins are highly effective ocular hypotensive agents,and are ideally suited for the long-term medical management of glaucoma(see, for example, Bito, L. Z. Biological Protection withProstaglandins, Cohen, M. M., ed., Boca Raton, Fla., CRC Press Inc.,;1985, pp. 231-252; and Bito, L. Z., Applied Pharmacology in the MedicalTreatment of Glaucomas Drance, S. M. and Neufeld, A. H. eds., New York,Grune & Stratton, 1984, pp. 477-505. Such prostaglandins includePGF_(2α), PGF_(1α), PGE₂, and certain lipid-soluble esters, such as C₁to C₂ alkyl esters, e.g. 1-isopropyl ester, of such compounds.

[0011] Although the precise mechanism is not yet known experimentalresults indicate that the prostaglandin-induced reduction in intraocularpressure results from increased uveoscleral outflow [Nilsson et. al.,Invest. Ophthalmol. Vis. Sci. (suppl), 284 (1987)].

[0012] The isopropyl ester of PGF_(2α) has been shown to havesignificantly greater hypotensive potency than the parent compound,presumably as a result of its more effective penetration through thecornea. In 1987, this compound was described as “the most potent ocularhypotensive agent ever reported” [see, for example, Bito, L. Z., Arch.Ophthalmol. 105, 1036 (1987), and Siebold et al., Prodrug 53 (1989)].

[0013] Whereas prostaglandins appear to be devoid of significantintraocular side effects, ocular surface (conjunctival) hyperemia andforeign-body sensation have been consistently associated with thetopical ocular use of such compounds, in particular PGF_(2α) and itsprodrugs, e.g., its 1-isopropyl ester, in humans. The clinicalpotentials of prostaglandins in the management of conditions associatedwith increased ocular pressure, e.g. glaucoma are greatly limited bythese side effects.

[0014] In a series of co-pending United States patent applicationsassigned to Allergan, Inc. prostaglandin esters with increased ocularhypotensive activity accompanied with no or substantially reducedside-effects are disclosed. The cop-ending U.S. Ser. No. 596,430 (filed10 Oct. 1990, now U.S. Pat. No. 5,446,041), relates to certain11-acyl-prostaglandins, such as 11-pivaloyl, 11-acetyl, 11-isobutyryl,11-valeryl, and 11-isovaleryl PGF_(2α). Intraocular pressure reducing15-acyl prostaglandins are disclosed in the co-pending application U.S.Ser. No. 175,476 (filed 29 Dec. 1993). Similarly, 11,15-9,15 and9,11-diesters of prostaglandins, for example 11,15-dipivaloyl PGF_(2α)are known to have ocular hypotensive activity. See the co-pending patentapplications U.S. Ser. No. 385,645 (filed 07 Jul. 1989, now U.S. Pat.No. 4,994,274), Ser. No. 584,370 (filed 18 Sep. 1990, now U.S. Pat. No.5,028,624) and Ser. No. 585,284 (filed 18 Sep. 1990, now U.S. Pat. No.5,034,413). Recently, we have also shown that 17-napthyl andbenzothienyl prostaglandin compounds also have ocular hypotensiveactivity (U.S. Ser. No. 859,770, filed 17 May 2001). The disclosures ofall of these patent applications are hereby expressly incorporated byreference.

[0015] Certain 15,15-dimethyl prostaglandins with antihypertensive,gastric acid secretion inhibition, and smooth muscle stimulantproperties, are known to have improved metabolic stability. These aredescribed by Pernet et al in U.S. Pat. No. 4,117,014 (filed 23 Dec.1976), the disclosure of which is hereby expressly incorporated byreference.

SUMMARY OF THE INVENTION

[0016] The present invention concerns a method of treating ocularhypertension which comprises administering to a mammal having ocularhypertension a therapeutically effective amount of a compound of FormulaI

[0017] wherein the dashed line indicates the presence or absence of abond, the hatched wedge indicates the α (down) configuration, and thesolid triangle indicates the β (up) configuration;

[0018] B is a single, double, or triple covalent bond;

[0019] n is 0-6;

[0020] X is CH₂, S or O;

[0021] Y is any pharmaceutically acceptable salt Of CO₂H, or CO₂R,CONR₂, NHCH₂CH₂OH, N(CH₂CH₂OH)₂, CH₂OR, P(O)(OR)₂, CONRSO₂R, SONR₂, or

[0022] R is H, C₁₋₆ alkyl or C₂₋₆ alkenyl;

[0023] R² and R³ are C₁₋₆ linear alkyl which may be the same ordifferent, and may be bonded to each other such that they form a ringincorporating the carbon to which they are commonly attached;

[0024] R⁴ is hydrogen, R, C(═O)R, or any group that is easily removedunder physiological conditions such that R⁴ is effectively hydrogen;

[0025] R⁵ is hydrogen or R;

[0026] R⁶ is

[0027] i) hydrogen;

[0028] ii) a linear or branched hydrocarbon containing between 1 and 8carbon atoms, which may contain one or more double or triple bonds, oroxygen or halogen derivatives of said hydrocarbon, wherein 1-3 carbon orhydrogen atoms may be substituted by O or a halogen; or

[0029] iii) aryloxy, heteroaryloxy, C₃₋₈ cycloalkyloxy, C₃₋₈ cycloalkyl,C₆₋₁₀ aryl or C₃₋₁₀ heteroaryl, wherein one or more carbons issubstituted with N, O, or S; and which may contain one or moresubstituents selected from the group consisting of halogen,trihalomethyl, cyano, nitro, amino, hydroxy, C₆₋₁₀ aryl, C₃₋₁₀heteroaryl, aryloxy, heteroaryloxy, C₁₋₆ alkyl, OR, SR, and SO₂R.

[0030] In another aspect, the present invention relates to apharmaceutical product, comprising a container adapted to dispense itscontents in a metered form; and an ophthalmic solution therein, ashereinabove defined.

[0031] In another aspect, certain of the compounds represented by theabove formula, disclosed below and utilized in the method of the presentinvention are novel and unobvious.

[0032] In a further aspect, certain elements of the processes ofpreparing the compounds represented by the above formula and describedherein are novel and unobvious.

BRIEF DESCRIPTION OF THE DRAWING FIGURES

[0033] Schemes 1-7 illustrate possible ways to prepare compounds of theinvention.

DETAILED DESCRIPTION OF THE INVENTION

[0034] The present invention relates to the use of prostanoic acidderivatives as ocular hypotensives. The compounds used in accordancewith the present invention are encompassed by the following structuralformula I:

[0035] A preferred group of the compounds of the present inventionincludes compounds that do not have the following structural formula II:

[0036] wherein A is CO₂H or CO₂Me;

[0037] D is a single, double, or triple covalent bond;

[0038] E is a linear, branched, or cycloalkyl chain of 3 to 7 carbons,trifluoromethylbutyl, hydroxylalkyl, or CH₂R⁷ wherein R⁷ is phenyl,cyclopentyl, phenoxy, chlorophenoxy, propoxy, or —CH₂SCH₂CH₃;

[0039] J is hydrogen, R, C(═O)R, or any group that is easily removedunder physiological conditions such that R⁴ is effectively hydrogen; and

[0040] G is H or CH₃.

[0041] Another preferred group includes compounds having formula III:

[0042] Another preferred group includes compounds having formula IV:

[0043] Another preferred group includes compounds having formula V:

[0044] wherein at least one of R² and R³ is not methyl.

[0045] In the above formulae, the substituents and symbols are ashereinabove defined.

[0046] In the above formulae:

[0047] Preferably Y is any pharmaceutically acceptable salt of CO₂H orCO₂R. More preferably Y is CO₂H or CO₂Me.

[0048] Preferably n is 2.

[0049] Preferably, R⁶ is C₆₋₁₀ aryl or C₃₋₁₀ heteroaryl, which maycontain one or more substituents selected from the group consisting ofhalogen, trihalomethyl, cyano, nitro, amino, hydroxy, C₁₋₆alkyl, OR, SR,and SO₂R. More preferably R⁶ is phenyl, napthyl, benzofuranyl, orbenzothienyl, which may contain one or more substituents selected fromthe group consisting of halogen, trihalomethyl, cyano, nitro, amino,hydroxy, C₁₋₆ alkyl, OR, SR, and SO₂R. Most preferred is3-chlorobenzothien-2-yl.

[0050] Another preferred group includes compounds having formula XIII:

[0051] wherein B represents a single or double bond;

[0052] and R⁶ is napthyl, benzofuranyl, or benzothienyl, which maycontain one or more substituents selected from the group consisting ofhalogen, trihalomethyl, cyano, nitro, amino, hydroxy, C₁₋₆ alkyl, OR,SR, and SO₂R.

[0053] In another aspect of this invention, certain elements of themethod making the compounds of the invention are novel and unobvious.One such novel and unobvious element is the application of the use ofBaker's yeast as a reducing agent as reported by Brooks and coworkers(Brooks, et. al., “Asymmetric Microbial Reduction of Prochiral2,2-Disubstituted Cycloalkanediones”, J. Org. Chem., 1987, 52,3223-3232) in the synthesis of compounds of this invention. In thisnovel and unobvious application of this reaction, Baker's yeast is usedto carry out an asymmetric reduction of a compound of formula VII, whichis a 2,2-dialkylcyclopentane-1,3-dione, to a compound of formula VIII,which is a 2,2-dialkyl-3(S)-hydroxycyclopentanone. A compound of formulaVIII is then used to prepare compounds of this invention.

[0054] The two alkyl groups, R² and R³ of the compounds of formula VIand VII, in this reaction are the same as those defined for compounds ofFormula I above. In the case where the two alkyl groups are different, amixture of diastereomers is formed, which can be separated byconventional separation methods to obtain the enantiomerically pureproducts.

[0055] Preparation of 2,2-dialkylcyclopentan-1,3-diones is well known inthe art. One convenient way that a large variety of these compounds canbe prepared is by base-mediated alkylation of carbon-2 of thecyclopentane-1,3-dione using an alkyl halide or equivalent compound.This type of reaction is well known in the art. The preparation of threegeneral types of 2,2-dialkylcyclopentan-1,3-diones using this alkylationreaction is illustrated in Scheme 1. Compounds where one of the alkylgroups is methyl can be prepared by a simple alkylation reaction fromcommercially available 2-methylcyclopentan-1,3-dione 1 (Equation 1). Inthe case neither of the alkyl groups in the2,2-dialkylcyclopentan-1,3-dione are methyl (compound 2b), thesecompounds can be prepared from cyclopentan-1,3-dione by two consecutivealkylation reactions (Equation 2). In the case where the two alkylgroups in the 2,2-dialkylcyclopentan-1,3-dione are the same, thesealkylation reactions can be carried out in a one-pot procedure. In thecase where the two alkyl groups to form a cyclic compound incorporatingC₂ of the cyclopentanone into the ring, otherwise known as aspiroketone, these compounds can be prepared by using a dihaloalkane orequivalent compound to carry out a intermolecular alkylation followed byan intramolecular alkylation (Equation 3), which could be carried out ina one or two pot process. Those skilled in the art will recognize thatthere are many ways to prepare 2,2-dialkylcyclopentan-1,3-diones, andthe reactions of Scheme 1 are included to illustrate that thesecompounds can be readily prepared or obtained by those skilled in theart, and are not intended to limit the scope of the invention in anyway.

[0056] In another novel and unobvious aspect of this invention,compounds of the invention represented by Formula VM are prepared by aprocess that comprises the following steps:

[0057] i) reacting a compound of Formula IX with a compound of Formula Xin the presence of a suitable base to form a compound of Formula XI;

[0058] ii) coupling a compound of Formula XI with a compound of FormulaXII; and

[0059] iii) removing the protecting groups and separating thediastereomers to obtain the desired products;

[0060] wherein the hatched wedges indicate the α (down) configuration,the solid triangles indicate the β (up) configuration, and the wavylines indicate either the cis (Z) or trans (Z) conformation;

[0061] n is 0-6;

[0062] B is a single, double, or triple covalent bond;

[0063] J is a protecting group that can be easily removed to form therespective hydroxide group without affecting the rest of the molecule;

[0064] R is C₁₋₆ alkyl or C₂₋₆ alkenyl;

[0065] R² and R³ are C₁₋₆ linear alkyl which may be the same ordifferent, and may be bonded to each other such that they form a ringincorporating the carbon to which they are commonly attached;

[0066] X is S or O; and

[0067] M is a group that comprises one or more metal atoms.

[0068] All of the compounds encompassed by this invention can beprepared using the methods described above supplemented by methods knownto those skilled in the art. The synthesis of several compounds of theinvention is illustrated in Schemes 2-7. These Schemes that are includedherein are merely illustrative and are not intended to limit the scopeof the invention in any way. Although there are several ways thereduction of compounds of Formula VI to Formula VII could beincorporated into the synthesis of these compounds, one convenient wayto this is shown in Scheme 2. In this Scheme, compound 2 is a compoundof Formula VI and compound 3 is a compound of formula VII. However,those skilled in the art will recognize that there are many ways inwhich the reduction could be used to prepare compounds of thisinvention. TABLE 1 Low Rf High Rf Structure diastereomer diastereomer

21 22

23 24

34 35

36 37

38 39

40 41

42

43

44

45

46 47

48 49

50 51

52 53

54 55

56 57

58 59

60 61

62 63

64 65

66 67

[0069] The compounds named below, and illustrated in Table 1, areespecially preferred representatives of the compounds of the presentinvention:

[0070](3-{(1R,4S,5S)-5-(3-chloro-benzo[b]thiophen-2-yl)-3-hydroxy-pent-1-enyl]-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentylsulfanyl}-propylsulfanyl)-aceticacid methyl ester (21, 22);

[0071](3-{(1R,4S,5S)-5-(3-chloro-benzo[b]thiophen-2-yl)-3-hydroxy-pent-1-enyl]-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentylsulfanyl}-propylsulfanyl)-aceticacid (23, 24);

[0072](Z)-7-{(1R,4S,5R)-5-[(E)-5-(3-chloro-benzo[b]thiophene-2-yl)-3-hydroxy-pent-1-enyl]-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl}-hept-5-ynoicacid methyl ester (34, 35);

[0073](Z)-7-{(1R,4S,5R)-5-[(E)-5-(3-chloro-benzo[b]thiophene-2-yl)-3-hydroxy-pent-1-enyl]-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl}-hept-5-ynoicacid (36,37);

[0074](Z)-7-{(1R,4S,5R)-5-[(E)-5-(3-chloro-benzo[b]thiophene-2-yl)-3-hydroxy-pent-1-enyl]-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl}-hept-5-enoicacid methyl ester (38,39);

[0075](Z)-7-{(1R,4S,5R)-5-[(E)-5-(3-chloro-benzo[b]thiophene-2-yl)-3-hydroxy-pent-1-enyl]-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl}-hept-5-enoicacid (40,41);

[0076]7-[(1R,4S,5R)-4-Hydroxy-5-((E)-(S)-3-hydroxy-oct-1-enyl)-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-ynoicacid methyl ester (42)

[0077]7-[(1R,4S,5R)-4-Hydroxy-5-((E)-(S)-3-hydroxy-oct-1-enyl)-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-ynoicacid (43)

[0078](Z)-7-[(1R,4S,5R)-4-Hydroxy-5-((E)-(S)-3-hydroxy-oct-1-enyl)-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-enoicacid (44)

[0079](Z)-7-[(1R,4S,5R)-4-Hydroxy-5-((E)-(S)-3-hydroxy-oct-1-enyl)-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-enoicacid methyl ester (45)

[0080](Z)-7-[(1R,4S,5R)-4-Hydroxy-5-((E)-3-hydroxy-4-phenyl-but-1-enyl)-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-enoicacid (46, 47)

[0081](Z)-7-[(1R,4S,5R)-4-Hydroxy-5-((E)-3-hydroxy-4-phenyl-but-1-enyl)-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-enoicacid methyl ester (48, 49)

[0082](Z)-7-[(1R,4S,5R)-4-Hydroxy-5-((E)-3-hydroxy-5-phenyl-pent-1-enyl)-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-enoicacid methyl ester (50,51)

[0083](Z)-7-[(1R,4S,5R)-4-Hydroxy-5-((E)-3-hydroxy-5-phenyl-pent-1-enyl)-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-enoicacid (52,53)

[0084](Z)-7-[(1R,4S,5R)-5-((E)-4-Benzo[b]thiophen-2-yl-3-hydroxy-but-1-enyl)-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-enoicacid (54,55)

[0085]7-[(1R,4S,5R)-5-((E)-4-Benzo[b]thiophen-2-yl-3-hydroxy-but-1-enyl)-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl]-heptanoicacid (56,57)

[0086](Z)-7-[(1R,4S,5R)-5-(4-Benzo[b]thiophen-2-yl-3-hydroxy-butyl)-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-enoicacid (58,59)

[0087](Z)-7-[(1R,4S,5R)-5-((E)-4-Benzo[b]thiophen-2-yl-3-hydroxy-but-1-enyl)-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-enoicacid ethylamide (60,61)

[0088](Z)-7-[(1R,4S,5R)-5-((E)-4-Benzo[b]thiophen-2-yl-3-hydroxy-but-1-enyl)-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-enoicacid diethylamide (62,63)

[0089](Z)-7-[(1R,4S,5R)-5-((E)-4-Benzo[b]thiophen-2-yl-3-hydroxy-but-1-enyl)-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-enoicacid (2-hydroxy-ethyl)amide (64,65)

[0090](3S,4R,5R)-4-((E)-4-Benzo[b]thiophen-2-yl-3-hydroxy-but-1-enyl)-3-hydroxy-2,2-dimethyl-5-[(Z)-6-(1-H-tetrazol-5-yl)-hex-2-enyl]-cyclopentanone(66,67)

[0091] Pharmaceutical compositions may be prepared by combining atherapeutically effective amount of at least one compound according tothe present invention, or a pharmaceutically acceptable acid additionsalt thereof, as an active ingredient, with conventional ophthalmicallyacceptable pharmaceutical excipients, and by preparation of unit dosageforms suitable for topical ocular use. The therapeutically efficientamount typically is between about 0.0001 and about 5% (w/v), preferablyabout 0.001 to about 1.0% (w/v) in liquid formulations.

[0092] For ophthalmic application, preferably solutions are preparedusing a physiological saline solution as a major vehicle. The pH of suchophthalmic solutions should preferably be maintained between 6.5 and 7.2with an appropriate buffer system. The formulations may also containconventional, pharmaceutically acceptable preservatives, stabilizers andsurfactants.

[0093] Preferred preservatives that may be used in the pharmaceuticalcompositions of the present invention include, but are not limited to,benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetateand phenylmercuric nitrate. A preferred surfactant is, for example,Tween 80. Likewise, various preferred vehicles may be used in theophthalmic preparations of the present invention. These vehiclesinclude, but are not limited to, polyvinyl alcohol, povidone,hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose,hydroxyethyl cellulose and purified water.

[0094] Tonicity adjustors may be added as needed or convenient. Theyinclude, but are not limited to, salts, particularly sodium chloride,potassium chloride, mannitol and glycerin, or any other suitableophthalmically acceptable tonicity adjustor.

[0095] Various buffers and means for adjusting pH may be used so long asthe resulting preparation is ophthalmically acceptable. Accordingly,buffers include acetate buffers, citrate buffers, phosphate buffers andborate buffers. Acids or bases may be used to adjust the pH of theseformulations as needed.

[0096] In a similar vein, an ophthalmically acceptable antioxidant foruse in the present invention includes, but is not limited to, sodiummetabisulfite, sodium thiosulfate, acetylcysteine, butylatedhydroxyanisole and butylated hydroxytoluene.

[0097] Other excipient components which may be included in theophthalmic preparations are chelating agents. The preferred chelatingagent is edentate disodium, although other chelating agents may also beused in place or in conjunction with it.

[0098] The ingredients are usually used in the following amounts:Ingredient Amount (% w/v) active ingredient about 0.001-5 preservative  0-0.10 vehicle   0-40 tonicity adjustor   1-10 buffer 0.01-10 pHadjustor q.s. pH 4.5-7.5 antioxidant as needed surfactant as neededpurified water as needed to make 100%

[0099] The actual dose of the active compounds of the present inventiondepends on the specific compound, and on the condition to be treated;the selection of the appropriate dose is well within the knowledge ofthe skilled artisan.

[0100] The ophthalmic formulations of the present invention areconveniently packaged in forms suitable for metered application, such asin containers equipped with a dropper, to facilitate the application tothe eye. Containers suitable for dropwise application are usually madeof suitable inert, non-toxic plastic material, and generally containbetween about 0.5 and about 15 ml solution.

SYNTHETIC EXAMPLES

[0101] The methods of preparing compounds of this invention are furtherillustrated by the following non-limiting Examples, which are summarizedin the reaction schemes of FIGS. 1-7 wherein the compounds areidentified by the same designator in both the Examples and the Figures.

[0102] 2-Alkyl-cyclopentane-1,3-dione (1a). A mixture of1,3-cyclopentanedione (89.4 mmol, Aldrich), I—R² (96.4 mmol, Aldrich),and KOH (5.097 g, 90.8 mmol) in H₂O (25 mL)/dioxane (75 mL) is heated atreflux. After 5 h, a solution of KOH (2 g) and I—R² (2 mmol) in H₂O (5mL)/dioxane (15 mL) is added and after another 3 h at reflux thesolution is allowed to stir at room temperature overnight. In themorning, the reaction is continued by addition of a solution of KOH (2g) and I—R² (2.4 mmol) in H₂O (5 mL)/dioxane (15 mL) and heating atreflux. After 4 h, the mixture is allowed to cool to room temperatureand is extracted with ether (1×100 mL, 3×75 mL). The combined etherextracts are evaporated, the residue is combined with HCl (50 mL 10%),and the resulting mixture is placed in a 120° C. oil bath until boilingis observed (ca. 15 min.). The mixture is then allowed to cool to roomtemperature, is neutralized by addition of NaHCO₃ solution (150 mL,saturated) and the resulting mixture is then extracted with CH₂Cl₂ (4×75mL). The combined CH₂Cl₂ solution is dried (MgSO₄), filtered andevaporated to leave a brown oil which is used directly in the next step.

[0103] 2-Alkyl-2-methyl-cyclopentane-1,3-dione (2a). A mixture of2-methyl-1,3-cyclopentanedione (10.025 g, 89.4 mmol, Aldrich), I—R²(96.4 mmol, Aldrich), and KOH (5.097 g, 90.8 mmol) in H₂O (25mL)/dioxane (75 mL) is heated at reflux. After 5 h, a solution of KOH (2g) and I—R² (2 mmol) in H₂O (5 mL)/dioxane (15 mL) is added and afteranother 3 h at reflux the solution is allowed to stir at roomtemperature overnight. In the morning, the reaction is continued byaddition of a solution of KOH (2 g) and I—R² (2.4 mmol) in H₂O (5mL)/dioxane (15 mL) and heating at reflux. After 4 h, the mixture isallowed to cool to room temperature and is extracted with ether (1×100mL, 3×75 mL). The combined ether extracts are evaporated, the residue iscombined with HCl (50 mL 10%), and the resulting mixture is placed in a120° C. oil bath until boiling is observed (ca. 15 min.). The mixture isthen allowed to cool to room temperature, is neutralized by addition ofNaHCO₃ solution (150 μL, saturated) and the resulting mixture is thenextracted with CH₂Cl₂ (4×75 mL). The combined CH₂Cl₂ solution is dried(MgSO₄), filtered and evaporated to leave a brown oil which is useddirectly in the next step.

[0104] 2,2-Dialkyl-methyl-cyclopentane-1,3-dione (2b). A mixture of2-alkyl-1,3-cyclopentanedione 1a (89.4 mmol, Aldrich), I—R³ (96.4 mmol,Aldrich), and KOH (5.097 g, 90.8 mmol) in H₂O (25 mL)/dioxane (75 mL) isheated at reflux. After 5 h, a solution of KOH (2 g) and I—R³ (2 mmol)in H₂O (5 mL)/dioxane (15 mL) is added and after another 3 h at refluxthe solution is allowed to stir at room temperature overnight. In themorning, the reaction is continued by addition of a solution of KOH (2g) and I—R³ (2.4 mmol) in H₂O (5 mL)/dioxane (15 mL) and heating atreflux. After 4 h, the mixture is allowed to cool to room temperatureand is extracted with ether (1×100 mL, 3×75 mL). The combined etherextracts are evaporated, the residue is combined with HCl (50 mL 10%),and the resulting mixture is placed in a 120° C. oil bath until boilingis observed (ca. 15 min.). The mixture is then allowed to cool to roomtemperature, is neutralized by addition of NaHCO₃ solution (150 mL,saturated) and the resulting mixture is then extracted with CH₂Cl₂ (4×75mL). The combined CH₂Cl₂ solution is dried (MgSO₄), filtered andevaporated to leave a brown oil which is used directly in the next step.

[0105] Spiro[2.4]heptane-4,7-dione (2c). A mixture of2-alkyl-1,3-cyclopentanedione 1a (89.4 mmol, Aldrich), 1,2-dibromoethane(120 mmol, Aldrich), and KOH (5.097 g, 90.8 mmol) in H₂O (25 mL)/dioxane(75 mL) is heated at reflux for 24 hours. The mixture is allowed tocool, and the crude product is extracted with ether (1×100 mL, 3×75 mL).The combined ether extracts are evaporated, the residue is combined withHCl (50 mL 10%), and the resulting mixture is placed in a 120° C. oilbath until boiling is observed (ca. 15 min.). The mixture is thenallowed to cool to room temperature, is neutralized by addition ofNaHCO₃ solution (150 mL, saturated) and the resulting mixture is thenextracted with CH₂Cl₂ (4×75 mL). The combined CH₂Cl₂ solution is dried(MgSO₄), filtered and evaporated to leave a brown oil which is useddirectly in the next step.

[0106] 2,2-Dimethyl-cyclopentane-1,3-dione (2). The published procedurewas followed. (Agosta, W. C.; Smith, A. B. J. Org. Chem. 1970, 35, 3856)A mixture of 2-methyl-1,3-cyclopentanedione (10.025 g, 89.4 mmol,Aldrich), methyl iodide (6.0 mL, 96.4 mmol, Aldrich), and KOH (5.097 g,90.8 mmol) in H₂O (25 mL)/dioxane (75 mL) was heated at reflux. After 5h, a solution of KOH (2 g) and MeI (2.4 mL) in H₂O (5 mL)/dioxane (15mL) was added and after another 3 h at reflux the solution was allowedto stir at room temperature overnight. In the morning, the reaction wascontinued by addition of a solution of KOH (2 g) and MeI (2.4 mL) in H₂O(5 mL)/dioxane (15 mL) and heating at reflux. After 4 h, the mixture wasallowed to cool to room temperature and was extracted with ether (1×100mL, 3×75 mL). The combined ether extracts were evaporated, the residuecombined with HCl (50 mL 10%), and the resulting mixture was placed in a120° C. oil bath until boiling was observed (ca. 15 min.). The mixturewas then allowed to cool to room temperature, was neutralized byaddition of NaHCO₃ solution (150 mL, saturated) and the resultingmixture then extracted with CH₂Cl₂ (4×75 mL). The combined CH₂Cl₂solution was dried (MgSO₄), filtered and evaporated to leave a brown oil(10.474 g, 83 mmol, 93%) which was used directly in the next step.

[0107] (S)-3-Hydroxy-2,2-dimethyl-cyclopentanone (3). The publishedprocedure was followed. (Brooks, D. W.; Hormoz, M.; Grothaus, P. G. J.Org. Chem. 1987, 52, 3223) A 35° C. (internal temperature) solution ofD-glucose (106.73 g, 592 mmol, Aldrich) in H₂O (690 mL) in a 4 LErlenmeyer was treated with baker's yeast (71.065 g, Fleischmann's). Themixture was allowed to ferment for 2 h, then2,2-dimethyl-cyclopentane-1,3-dione (2) (7.316 g, 58 mmol) was added.

[0108] The mixture was stirred for 48 h and then filtered throughcelite, washing with about 1 L CH₂Cl₂. The filtration was difficult dueto the thick consistency of the yeast and it helped to continually addCH₂Cl₂ to the mixture and scrape the top of the celite layer with aspatula. The filtrate was transferred to a separatory funnel, and 100 mLbrine was added and the layers were separated. Brine (400 mL) was addedto the aqueous layer and the resulting solution extracted further withCH₂Cl₂ (3×500 mL). The combined CH₂Cl₂ solution was dried (MgSO₄),filtered and evaporated to leave a yellow oil. Flash chromatography(11×5 cm, 20% EtOAc/hexs→25%→30%→40%→50%) gave alcohol 3 (2.435 g, 19mmol, 33%).

[0109] The enantiomeric excess of 3 was assayed by ¹H NMR of thecorresponding Mosher's ester which was prepared by treatment of alcohol3 (11 mg, 0.09 mmol) in dichloroethane (0.3 mL, Aldrich) with pyridine(27 μL, 0.33 mmol, Aldrich) and(R)-α-methoxy-α-trifluoromethyphenylacetic acid chloride (58 μL, 0.31mmol, Fluka). The mixture was stirred overnight and then partitionedbetween water (10 mL) and ether (10 mL). The ether layer was washed with1 M HCl (10 mL) and saturated NaHCO₃ solution and then was dried(MgSO₄), filtered and evaporated. ¹H NMR analysis was done on the crudeester.

[0110](S)-3-(tert)-Butyl-dimethyl-silanyloxy-2,2-dimethyl-cyclopentanone (4).A solution of alcohol 3 (520 mg, 4.1 mmol) and 2,6-lutidine (0.56 mL,4.8 mmol, Aldrich) in CH₂Cl₂ (8.0 mL, Aldrich) was treated with TBSOTf(1.0 mL, 4.3 mmol, Aldrich). After 5.5 h, saturated NaHCO₃ solution (20mL) was added and the mixture extracted with CH₂Cl₂ (20 mL). The CH₂Cl₂solution was washed with 20 mL each of 1 M HCl, saturated NaHCO₃solution, and brine and then was dried (MgSO₄), filtered and evaporated.Flash chromatography (5×5 cm, 10% Et₂O/pentane) gave TBS ether 4 (698mg, 2.9 mmol, 70%).

[0111](S)-3-(tert)-Butyl-dimethyl-silanyloxy-2,2-dimethyl-5-phenylselanyl-cyclopentanone(5). A solution of TBS ether 4 (1.496 g, 6.2 mmol) in THF (2 mL,Aldrich) was added dropwise to a −78° C. solution of LDA (4.9 mL, 7.3mmol, 1.5 M/cyclohexane, Aldrich) in THF (22 mL, Aldrich), rinsing with2 mL THF. After 15 min., a solution of PhSeCl (1.424 g, 7.4 mmol,Aldrich) in THF (2 mL) was quickly added by cannula, rinsing with 2 mLTHF. The solution was stirred for 10 min. and then partitioned between50 mL 0.5 M HCl and 75 mL ether. The ether layer was washed with 30 mLeach of water, saturated NaHCO₃ solution, and brine and then was dried(MgSO₄), filtered and evaporated. Flash chromatography (2%EtOAc/hexs→4%) gave phenylselenide 5 (1.641 g, 4.1 mmol, 67%) along with476 mg of mixed fractions containing a lower R_(f) impurity.

[0112](S)-4-(tert)-Butyl-dimethyl-silanyloxy-5,5-dimethyl-cyclopent-2-enone(6).A solution of selenide 5 (1.641 g, 4.1 mmol) and pyridine (0.62 mL, 7.7mmol, Aldrich) in CH₂Cl₂ (13 mL, Aldrich) was treated with H₂O (1 mL)and 30% H₂O₂ (1.1 mL, Aldrich). The mixture was stirred for 30 min. andthen was partitioned between 25 mL CH₂Cl₂ and 25 mL saturated NaHCO₃solution. The aqueous layer was extracted with 25 mL CH₂Cl₂ and thecombined CH₂Cl₂ solution washed with 1 M HCl (2×25 mL) and brine (50mL). The solution was then dried (MgSO₄), filtered and evaporated toleave an orange oil. Flash chromatography (6×4 cm, 10% ether/pentane)gave enone 6 (572 mg, 2.4 mmol, 59%).

[0113] (3-Mercapto-propylsulfanyl)-acetic acid methyl ester (8). Anice-cold solution of 1,3-dithiane (2.0 mL, 19.9 mmol) in THF (40 mL) wastreated with NaH (819 mg, 20.5 mmol). After 30 min., methyl bromoacetate(1.9 mL, 20.0 mmol) was added and the mixture stirred for 3.5 h at roomtemperature. The reaction was quenched by addition of MeOH and then 50mL 1 M HCl. The mixture was extracted with ether (2×50 mL) and thecombined ether solution washed with saturated sodium bicarbonatesolution (50 mL) and brine (50 mL) and then was dried (MgSO₄), filteredand evaporated. Purification by flash chromatography on silica gel(10-15% ethyl acetate/hexanes) gave 971 mg (5.38 mmol, 27%) of thethiol.

[0114]{3-[(S)-3-(tert)-Butyl-dimethyl-silanyloxy)-4,4-dimethyl-5-oxo-cyclopent-1-enylsulfanyl]-propylsulfanyl}-aceticacid methyl ester (10). A solution of enone 6 (156 mg, 0.65 mmol) inMeOH (4.3 mL) was treated with 30% H₂O₂ (0.21 mL) and 1 M NaOH (32 μL).After 4 h, 20 mL saturated ammonium chloride solution was added and themixture was extracted with dichloromethane (3×10 mL). The combineddichloromethane solution was dried (Na₂SO₄), filtered and evaporated invacuo.

[0115] A solution of thiol 8 (110 mg, 0.61 mmol) in dichloromethane (3mL) was added to the crude epoxide (9) by cannula, rinsing with 1.2 mL.Basic alumina (628 mg) was added and the mixture stirred for 16 h. Thesolvent was evaporated and purification of the residue by flashchromatography on silica gel (15% ethyl acetate/hexanes) gave 129 mg(0.31 mmol, 48%) of the coupled enone (10).

[0116] (3-Chloro-benzo[b]thiophen-2-yl)-methanol (12). To an ice coldsolution of 10.0 g (47.0 mmol) of3-chloro-benzo[b]thiophene-2-carboxylic acid (11) in 200 mL of THF wasadded 47 mL of LiAlH₄ (47 mmol, 1 M/THF). After 3 h, the reaction wasquenched by addition of MeOH (ca. 40 mL). The volatiles were evaporatedand the residue was treated with 50 mL 1 M HCl. After stirring for 10min., the mixture was extracted with CH₂Cl₂ (3×150 ml). The combinedCH₂Cl₂ solution was dried (MgSO₄), filtered and evaporated. Purificationby flash chromatography on silica gel (10-20% ethyl acetate/hexane) gave4.32 g (21.6 mmol, 46%) of the alcohol (12).

[0117] 3-Chloro-benzo[b]thiophene-2-carbaldehyde (13). A solution ofalcohol 12 (4.32 g, 21.6 mmol) in 40 mL of CH₂Cl₂ was treated with 4Amolecular sieves, NMO (3.81 g, 32.5 mmol), and TPAP (381 mg, 1.08 mmol).The reaction was stirred for 10 min. and then was evaporated to dryness.Purification by flash chromatography on silica gel (2% ethylacetate/hexane) gave 3.52 g (18.3 mmol, 84%) of the aldehyde (13).

[0118] (E)-3-(3-Chloro-benzo[b]thiophen-2-yl)-acrylic acid methyl ester(14). A solution of 3.52 g (18.3 mmol) of 13 in 50 mL toluene wastreated with methyl(triphenylphosphoranylidene)acetate (7.48 g, 21.9mmol). After 4 h, saturated NaHCO₃ solution (50 mL) was added and themixture extracted with ethyl acetate (2×75 mL). The combined ethylacetate solution was washed with brine (50 mL), dried (Na₂SO₄), filteredand evaporated. Purification by flash chromatography on silica gel (5%ethyl acetate/hexane) provided 3.60 g (14.6 mmol, 80%) of the enoate(14).

[0119] 3-(3-Chloro-benzo[b]thiophen-2-yl)-propionic acid methyl ester(15). A solution of 3.60 g (14.6 mmol) of 14 in 50 mL THF was treatedwith Wilkinson's catalyst (3.35 g, 3.62 mmol). The mixture was stirredunder 1 atm H₂ for 18 h and then was filtered through celite. Thesolvent was evaporated and the residue purified by flash chromatographyon silica gel (O₂% ethyl acetate/hexane) to give 3.63 g (14.3 mmol 99%)of the saturated ester (15).

[0120] 3-(3-Chloro-benzo[b]thiophen-2-yl)-propan-1-ol (16). An ice coldsolution of 3.63 g (14.3 mmol) of 15 in 60 mL of ether was treated withLiBH₄ (621 mg, 28.5 mmol) and methanol (2 mL). After 30 min., 30 mL of0.5 M NaOH solution was added. The mixture was extracted with ethylacetate (2×25 mL) and the combined ethyl acetate solution washed withbrine (50 mL), dried (MgSO₄), filtered and evaporated. The residue waspurified by flash chromatography on silica gel (5-20% ethylacetate/hexane) to give 2.57 g (11.3 mmol, 79%) of the alcohol (16).

[0121] 3-(3-Chloro-benzo[b]thiophen-2-yl)-propionaldehyde (17). A −78°C. solution of oxalyl chloride (1.73 g, 13.6 mmol) in dichloromethane(20 mL) was treated with DMSO (20 mL). After 5 min., a solution ofalcohol 16 (2.57 g, 11.3 mmol) in dichloromethane (20 mL) was added.After another 15 min., triethylamine (7.1 mL, 50.6 mmol) was added. Thereaction was stirred at −78° C. for 5 min., and then allowed to warm toroom temperature. After 30 min., 100 mL water was added and the mixtureextracted with dichloromethane (3×60 mL). The combined dichloromethanesolution was dried (Na₂SO₄), filtered and evaporated. Purification byflash chromatography on silica gel (10% ethyl acetate/hexane) gave 2.11g (9.4 mmol, 83%) of the aldehyde (17).

[0122] 5-(3-Chloro-benzo[b]thiophen-2-yl)-pent-1-yn-3-ol (18). Asolution of aldehyde 17 (2.11 g, 9.4 mmol) in 15 mL THF was added to asolution of ethynylmagnesium bromide (28.2 mL, 14.1 mmol, 0.5 M THF) at0° C. After 1.5 h, saturated NH₄Cl solution (75 mL) was added and themixture was extracted with ethyl acetate (3×50 mL). The combined ethylacetate solution was washed with brine (50 mL) and then was dried(Na₂SO₄), filtered and evaporated. Purification by flash chromatography(5-20% ethyl acetate/hexane) gave 2.20 g (8.78 mmol, 93%) of the alcohol(18).

[0123]tert-Butyl-{1-[2-(3-chloro-benzo[b]thiophen-2-yl)-ethyl]-prop-2-ynyloxy}-dimethyl-silane(19). A solution of alcohol 18 (2.20 g, 8.78 mmol) in dichloromethane(15 mL) was treated with DMAP (215 mg, 1.8 mmol), TBSCl (1.59 g, 10.5mmol), and triethylamine (1.8 mL, 13.2 mmol). The reaction was stirredfor 24 h and then saturated sodium bicarbonate solution (50 mL) wasadded. The mixture was extracted with dichloromethane (2×50 mL) and thecombined dichloromethane solution dried (Na₂SO₄), filtered andevaporated. Purification by flash chromatography (4% ethylacetate/hexane) gave 3.06 g (6.4 mmol, 73%) of the protected alcohol(19).

[0124](3-{(1R,4S,5S)-4-(tert-Butyl-dimethyl-silanyloxy)-5-[(E)-3-(tert-butyl-dimethyl-silanyloxy)-5-(3-chloro-benzo[b]thiophen-2-yl)-pent-1-enyl]-3,3-dimethyl-2-oxo-cyclopentylsulfanyl}-propylsulfanyl)-aceticacid methyl ester (20). A solution of alkyne 19 (105 mg, 0.28 mmol) inTHF (1.2 mL) was treated with bis(cyclopentadienyl)zirconium chloridehydride (91 mg, 0.35 mmol). The reaction was stirred for 30 min., thenwas cooled to −78° C. and treated with methyllithium (0.46 mL, 0.64mmol, 1.4 M in ether). After 10 min., a precooled (−78° C.) solution oflithium 2-thienylcyanocuprate (1.3 mL, 0.33 mmol, 0.25 M in THF) wasadded by cannula. The reaction was stirred for 45 min. and then enone 10(61 mg, 0.15 mmol) in 0.2 mL THF was added by cannula, rinsing with 0.2mL THF. After 1 h, The reaction was quenched by addition of 20 mL 1:1saturated ammonium chloride solution/concentrated ammonium hydroxide.The mixture was stirred for 45 min. and then was extracted with ethylacetate (3×20 mL). The combined ethyl acetate solution was dried(Na₂SO₄), filtered and evaporated. Purification by flash chromatographyon silica gel (10% ethyl acetate/hexanes) gave 51 mg (0.064 mmol, 43%)of the coupled product (20).

[0125](3-{([R,4S,5S)-5-(3-chloro-benzo[b]thiophen-2-yl)-3-hydroxy-pent-1-enyl]-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentylsulfanyl}-propylsulfanyl)-aceticacid methyl ester (21, 22). A solution of 20 (51 mg, 0.064 mmol) inCH₃CN (1.6 mL) was treated with HF-pyridine (0.26 mL). The reaction wasstirred for 24 h and then was quenched by addition of 15 mL saturatedsodium bicarbonate solution. The mixture was extracted withdichloromethane (3×10 mL) and the combined dichloromethane solution wasdried (Na₂SO₄), filtered and evaporated. Purification by preparativethin layer chromatography on silica gel (40% ethyl acetate/hexanes) gave12 mg (0.023 mmol, 71%) of each diastereomer.

[0126](3-{(1R,4S,5S)-5-(3-chloro-benzo[b]thiophen-2-yl)-3-hydroxy-pent-1-enyl]-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentylsulfanyl}-propylsulfanyl)-aceticacid (23, 24). Rabbit liver esterase (9 mg) was added to a solution ofthe lower R_(f) ester 21 (11 mg, 0.021 mmol) in pH 7.2 phosphate buffer(0.5 mL)/CH₃CN (0.1 mL). The mixture was stirred overnight and then 10mL 0.5 M HCl was added along with a few mL's of brine. The mixture wasextracted with ethyl acetate (3×10 mL) and the combined ethyl acetatesolution dried (Na₂SO₄), filtered and evaporated. Purification by flashchromatography on silica gel (3-5% MeOH/CH₂Cl₂) gave 4 mg (0.0078 mmol,37%) of the acid (23). 300 MHz ¹H NMR (CDCl₃, ppm) δ 7.73 (2H, d, J=8.4Hz) 7.4-7.3 (2H, m) 5.9-5.8 (1H, m) 5.8-5.7 (1H, m) 4.4-4.3 (1H, m) 3.63(1H, d, J=9.7 Hz) 3.21(2H, s) 3.1-2.4 (11H, overlapping m) 2.1-1.7 (4H,overlapping m) 1.12 (3H, s) 1.03 (3H, s).

[0127] The higher R_(f) ester was hydrolyzed similarly except a solutionof rabbit liver esterase (10 mg) in 0.5 mL of pH 7.2 phosphate bufferwas added to a solution of the ester (10 mg, 0.019 mmol) in CH₃CN (0.2mL). The reaction was stirred for 22 h and then worked up and purifiedas above. This gave 7 mg (0.013 mmol, 71%) of the acid (24). 300 MHz ¹HNMR (CDCl₃, ppm) δ 7.73 (2H, d, J=8.8 Hz) 7.44-7.31 (2H, m) 5.9-5.8 (1H,m) 5.8-5.7 (1H, m) 4.4-4.3 (1H, m) 3.64 (1H, d, J=9.7 Hz) 3.3-2.3 (13H,overlapping m) 2.1-1.7 (4H, overlapping m) 1.12 (3H, s) 1.03 (3H, s).

[0128] tert-Butyl-hex-5-ynyloxy-dimethyl-silane (26).

[0129] 7-(tert-Butyl-dimethyl-silanyloxy)-hept-2-yn-1-ol (27).

[0130] Acetic acid 7-(tert-butyl-dimethyl-silanyloxy)-hept-2-ynyl ester(28). A solution of 7-(tert-Butyl-dimethyl-silanyloxy)-hept-2-yn-1-ol 27(4.507 g, 21 mmol) in pyridine (20 mL) was treated with acetic anhydride(3.0 mL, 31.8 mmol). After 18 h, the solvent was evaporated and theresidue co-evaporated with toluene. The residue was used directly in thenext step.

[0131] 7-Acetoxy-hept-5-ynoic acid (29). A solution of crude 28 inacetone (100 mL) was treated with Jones Reagent (18.0 mL, 41.4 mmol, 2.3M). The mixture became warm and so was cooled with an ice bath. After 1h at room temperature, 10 mL isopropyl alcohol was added and the mixturestirred further for 15 min. The mixture still had a brown color soanother 10 mL isopropyl alcohol was added. After another 15 min., thecolor had not changed so the mixture was filtered through celite and thefiltrate evaporated in vacuo. The residue was partitioned between 100 mLether and 100 mL saturated ammonium chloride solution. The aqueous layerwas extracted with 100 mL ether and the combined ether solution washedwith brine and then was dried (MgSO₄), filtered and evaporated to leavea yellow oil (6.333 g) that was used directly in the next step.

[0132] 7-Hydroxy-hept-5-ynoic acid methyl ester (30). The crude acid 29(6.333 g) was treated with a 1% solution of acetyl chloride in methanol(60 mL). After 16 h, sodium bicarbonate (1.966 g, 23.4 mmol) was added.The mixture was dried (MgSO₄), filtered through celite and evaporated invacuo. Purification by flash chromatography on silica gel (30-40% ethylacetate/hexanes) gave 7-Hydroxy-hept-5-ynoic acid methyl ester 30 (3.022g, 19.3 mmol, 92% from 7-(tert-Butyl-dimethyl-silanyloxy)-hept-2-yn-1-ol27).

[0133] 7-Iodo-hept-5-ynoic acid methyl ester (31). A solution of 30(1.347 g, 8.6 mmol) in 5 mL dichloromethane was added to a mixture oftriphenylphosphine (2.725 g, 10.4 mmol), imidazole (726 mg, 10.7 mmol),and iodine (2.602 g, 10.3 mmol) in 34 mL dichloromethane, rinsing with 5mL dichloromethane. After 40 min., the dichloromethane was evaporated invacuo to a few mL's and the resulting mixture filtered through basicalumina, washing with 10% ethyl acetate/hexanes. Purification by flashchromatography on silica gel (10% ethyl acetate/hexanes) gave 1.878 g(7.1 mmol, 83%) of the propargyl iodide.

[0134]tert-Butyl-{(E)-1-[2-(3-chloro-benzo[b]thiophen-2-yl)-ethyl]-3-iodo-allyloxy}-dimethyl-silane(32). A solution of alkyne 19 (5.547 g, 15.2 mmol) in dichloromethane(50 mL) was treated with Cp₂ZrHCl (5.794 g, 22.5 mmol). The reaction wasstirred for 45 min. and then N-iodosuccinimide (4.966 g, 22.1 mmol) wasadded. After 15 min., saturated sodium bicarbonate solution (200 mL) wasadded and the mixture was extracted with dichloromethane (2×100 mL). Thecombined dichloromethane solution was dried (MgSO₄), filtered andevaporated. Purification by flash chromatography on silica gel (0-5%ethyl acetate/hexanes) gave 6.608 g (13.1 mmol, 86%) of the vinyl iodide(32).

[0135]7-{(1R,4S,5R)-4-(tert-Butyl-dimethyl-silanyloxy)-5-[(E)-3-(tert-butyl-dimethyl-silanyloxy)-5-(3-chloro-benzo[b]thiophen-2-yl)-pent-1-enyl]-3,3-dimethyl-2-oxo-cyclopentyl}-hept-5-ynoicacid methyl ester (33). A −78° C. solution of iodide 32 (675 mg, 1.34mmol) in THF (2.0 mL) was treated with tert-butyllithium (1.73 mL, 2.94mL, 1.7 M/pentane). The dark red mixture was stirred for 25 min. andthen dimethylzinc (0.80 mL, 1.6 mmol, 2 M/toluene) was added. Thesolution was stirred at 0° C. for 15 min. and then recooled to −78° C.At this time, a solution of enone 6 (208 mg, 0.87 mmol) in THF (1.0 mL)was added over 2 h by syringe pump, rinsing with 0.5 mL THF. After 30min., HMPA (1.34 mL, distilled from CaH₂) was added followed by asolution of propargyl iodide 31 (1.286 g, 4.83 mmol) in THF (1.0 mL).The solution was stirred in a 40° C. bath overnight and then 20 mLsaturated ammonium chloride solution and 10 mL water were added. Themixture was extracted with dichloromethane (20 mL) and ethyl acetate(2×20 mL). The combined organic extracts were dried (MgSO₄), filteredand evaporated. Purification by flash chromatography on silica gel(5-10% ethyl acetate/hexanes) gave 198 mg (0.27 mmol, 31%) of 33.

[0136](Z)-7-{(1R,4S,5R)-5-[(E)-5-(3-chloro-benzo[b]thiophene-2-yl)-3-hydroxy-pent-1-enyl]-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl}-hept-5-ynoicacid methyl ester (34, 35). A solution of 33 (198 mg, 0.27 mmol) inCH₃CN (6.5 mL) was treated with HF-pyridine (1.2 mL). The solution wasstirred for 3 h and saturated sodium bicarbonate solution (120 mL) wasadded. The mixture was extracted with dichloromethane (3×50 mL) and thecombined dichloromethane solution dried (Na₂SO₄), filtered andevaporated. Purification by flash chromatography (50% ethylacetate/hexane) followed by preparative TLC (55% ethyl acetate/hexane)gave 55 mg (0.11 mmol, 41%) of the less polar diastereomer (34) and 51mg (0.10 mmol, 37%) of the more polar diastereomer (35).

[0137](Z)-7-{(1R,4S,5R)-5-[(E)-5-(3-chloro-benzo[b]thiophene-2-yl)-3-hydroxy-pent-1-enyl]-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl}-hept-5-ynoicacid (low R_(f) diastereomer, 36). A solution of 34 (9 mg, 0.017 mmol)and rabbit liver esterase (1 mg) in pH 7.2 phosphate buffer (2 mL)/CH₃CN(0.1 mL) was stirred for 17 h. The mixture was then coevaporated withCH₃CN to remove water and the residue purified by flash chromatographyon silica gel (3-7% MeOH/CH₂Cl₂) to give 8 mg (0.016 mmol, 93%) of theacid (36).

[0138](Z)-7-{(1R,4S,5R)-5-[(E)-5-(3-chloro-benzo[b]thiophene-2-yl)-3-hydroxy-pent-1-enyl]-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl}-hept-5-ynoicacid (high R_(f) diastereomer, 37). A solution of 35 (12 mg, 0.023 mmol)and rabbit liver esterase (1 mg) in pH 7.2 phosphate buffer (2 mL)/CH₃CN(0.1 mL) was stirred for 17 h. TLC showed the presence of startingmaterial, so another 2 mg of the esterase was added. After stirring foranother 24 h, the reaction was complete. Work up and purification asabove for 36 gave 8 mg (0.016 mmol, 69%) of the acid (37).

[0139](Z)-7-{(1R,4S,5R)-5-[(E)-5-(3-chloro-benzo[b]thiophene-2-yl)-3-hydroxy-pent-1-enyl]-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl}-hept-5-enoicacid methyl ester (low R_(f) diastereomer, 38). Ethanol (95%, 2.5 mL)was added to NiCl₂ (50 mg, 0.39 mmol) and NaBH₄ (7 mg, 0.19 mmol). Theresulting black mixture was stirred for 5 min. and then ethylenediamine(41 μL, 0.61 mmol) was added. After 15 min., a solution of alkyne 34 (40mg, 0.077 mmol) in 0.5 mL 95% o ethanol was added, rinsing with 0.5 mLethanol. The flask was purged with H₂ and allowed to stir under 1 atm H₂for 22 h. The mixture was then filtered through celite and purified byflash chromatography on silica gel (55% ethyl acetate/hexanes) to give17 mg (0.032 mmol, 43%) of the alkene (38).

[0140](Z)-7-{(1R,4S,5R)-5-[(E)-5-(3-chloro-benzo[b]thiophene-2-yl)-3-hydroxy-pent-1-enyl]-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl}-hept-5-enoicacid methyl ester (high R_(f) diastereomer 39). The same procedure asfor 36 was followed to give 17 mg (0.032 mmol, 41%) of 39.

[0141](Z)-7-{(1R,4S,5R)-5-[(E)-5-(3-chloro-benzo[b]thiophene-2-yl)-3-hydroxy-pent-1-enyl]-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl}-hept-5-enoicacid (low R_(f) diastereomer, 40). The same procedure as above for 36,was used to give 9 mg (0.018 mmol, 85%) of acid 40.300 MHz ¹H NMR(CDCl₃, ppm) δ 7.73 (2H, d, J=8.4 Hz) 7.45-7.30 (2H, m) 5.8-5.6 (2H, m)5.4-5.3 (2H, m) 4.3-4.1(1H, m) 3.57 (1H, d, J=9.7 Hz) 3.1-2.9 (2H, m)2.5-1.9 (10H, m) 1.7-1.6 (2H, m) 1.09 (3H, s) 0.89 (3H, s).

[0142](Z)-7-{(1R,4S,5R)-5-[(E)-5-(3-chloro-benzo[b]thiophene-2-yl)-3-hydroxy-pent-1-enyl]-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl}-hept-5-enoicacid (high R_(f) diastereomer, 41). The same procedure as above for the36 was used to give 9 mg (0.018 mmol, 85%) of acid 41. 300 MHz ¹H NMR(CDCl₃, ppm) δ 7.73 (2H, d, J=8.8 Hz) 7.45-7.30 (2H, m) 5.8-5.6 (2H, m)5.45-5.30 (2H, m) 4.3-4.2 (1H, m) 3.61 (1H, d, J=9.7 Hz) 3.1-3.0(2H, m)2.5-1.9(10H, m) 1.7-1.6(2H, m) 1.10(3H, s) 0.90(3H, s).

[0143] The methods of screening the compounds of this invention for thedesired biological activity are illustrated in the followingnon-limiting examples. Results for example compounds of this inventionare included in Table 2. These results are presented purely forillustrative purposes and are not intended to limit the scope of theinvention in any way.

[0144] Radioligand Binding

Cells Stably Expressing EP₁, EP₂, EP₄ and FP Receptors

[0145] HEK-293 cells stably expressing the human or feline FP receptor,or EP₁, EP₂, or EP₄ receptors were washed with TME buffer, scraped fromthe bottom of the flasks, and homogenized for 30 sec using a Brinkman PT10/35 polytron. TME buffer Was added to achieve a final 40 ml volume inthe centrifuge tubes (the composition of TME is 100 mM TRIS base, 20 mMMgCl₂, 2M EDTA; 10N HCl is added to achieve a pH of 7.4).

[0146] The cell homogenate was centrifuged at 19000 r.p.m. for 20 min at4° C. using a Beckman Ti-60 rotor. The resultant pellet was resuspendedin TME buffer to give a final 1 mg/ml protein concentration, asdetermined by Biorad assay. Radioligand binding competition assays vs.[³H-]17-phenyl PGF₂(5 nM) were performed in a 100 μl volume for 60 min.Binding reactions were started by adding plasma membrane fraction. Thereaction was terminated by the addition of 4 ml ice-cold TRIS-HCl bufferand rapid filtration through glass fiber GF/B filters using a Brandelcell harvester. The filters were washed 3 times with ice-cold buffer andoven dried for one hour.

[0147] [³H-] PGE₂ (specific activity 180 Ci mmol) was used as theradioligand for EP receptors. [³H] 17-phenyl PGF_(2α) was employed forFP receptor binding studies. Binding studies employing EP₁, EP₂, EP₄ andFP receptors were performed in duplicate in at least three separateexperiments. A 200 μl assay volume was used. Incubations were for 60 minat 25° C. and were terminated by the addition of 4 ml of ice-cold 50 mMTRIS-HCl, followed by rapid filtration through Whatman GF/B filters andthree additional 4 ml washes in a cell harvester (Brandel). Competitionstudies were performed using a final concentration of 5 nM [³H]-PGE₂, or5 nM [³H] 17-phenyl PGF₂, and nonspecific binding determined with 10⁻⁵Mof unlabeled PGE₂, or 17-phenyl PGF_(2α), according to receptor subtypestudied.

[0148] Methods for FLIPR™ Studies

[0149] (a) Cell Culture

[0150] HEK-293(EBNA) cells, stably expressing one type or subtype ofrecombinant human prostaglandin receptors (prostaglandin receptorsexpressed: hDP/Gqs5; hEP₁; hEP₂/Gqs5; hEP_(3A)/Gqi5; hEP₄/Gqs5; hFP;hIP; hTP), were cultured in 100 mm culture dishes in high-glucose DMEMmedium containing 10% fetal bovine serum, 2 mM 1-glutamine, 250 μg/mlgeneticin (G418) and 200 μg/ml hygromycin B as selection markers, and100 units/ml penicillin G, 100 μg/ml streptomycin and 0.25 μg/mlamphotericin B.

[0151] (b) Calcium Signal Studies on the FLIPR™

[0152] Cells were seeded at a density of 5×10⁴ cells per well inBiocoat® Poly-D-lysine-coated black-wall, clear-bottom 96-well plates(Becton-Dickinson) and allowed to attach overnight in an incubator at37° C. Cells were then washed two times with HBSS-HEPES buffer (HanksBalanced Salt Solution without bicarbonate and phenol red, 20 nM HEPES,pH 7.4) using a Denley Cellwash plate washer (Labsystems). After 45minutes of dye-loading in the dark, using the calcium-sensitive dyeFluo-4 AM at a final concentration of 2 μM, plates were washed fourtimes with HBSS-HEPES buffer to remove excess dye leaving 100 μl in eachwell. Plates were re-equilibrated to 37° C. for a few minutes.

[0153] Cells were excited with an Argon laser at 488 nm, and emissionwas measured through a 510-570 nm bandwidth emission filter (FLIPR™,Molecular Devices, Sunnyvale, Calif.). Drug solution was added in a 50μl volume to each well to give the desired final concentration. The peakincrease in fluorescence intensity was recorded for each well. On eachplate, four wells each served as negative (HBSS-HEPES buffer) andpositive controls (standard agonists: BW245C (hDP); PGE₂ (hEP₁;hEP₂/Gqs5; hEP_(3A)/Gqi5; hEP₄/Gqs5); PGF_(2α) (hFP); carbacyclin (hIP);U-46619 (hTP), depending on receptor). The peak fluorescence change ineach drug-containing well was then expressed relative to the controls.

[0154] Compounds were tested in a high-throughput (HTS) orconcentration-response (CoRe) format. In the HTS format, forty-fourcompounds per plate were examined in duplicates at a concentration of10⁻⁵ M. To generate concentration-response curves, four compounds perplate were tested in duplicates in a concentration range between 10⁻⁵and 10⁻¹¹ M. The duplicate values were averaged. In either, HTS or CoReformat each compound was tested on at least 3 separate plates usingcells from different passages to give an n≧3. TABLE 2 hEP_(3D) CompoundhFP hEP₁ hEP₂ hEP_(3A) hEP₄ hDP hIP hTP 21 NA NA >10 K NA 98 NA NA NA 22NA NA NA NA 300 NA NA NA NA NA 30 23 NA NA NA >10 K 44 NA NA >10 K NA NA0.1 24 NA NA NA >>10 K 26 NA NA NA NA NA 0.1 34 NA NA NA >10 K NA NA >10K 35 NA NA 2455 NA NA 36 NA NA NA 200 >10 K NA 66 37 NA NA NA 100 >10 KNA 32 38 NA NA NA 2700 NA NA 269 39 NA NA NA 2300 NA NA 141 40 NA NA NA200 NA >10 K 0.3 41 NA >10 K NA 20 NA >10 K 42 NA NA NA >10⁴ >10⁴ NA NANA NA 559 NA 43 NA  >10⁴ NA 1700 400 3981 18 NA 11 63 44 NA 782 1500 3005.5 >10 K  284 18  944 4.6 0.2 45 NA NA NA >10⁴ 400 NA NA 631  NA 531 51NA NA 46 NA 290 >10 K >10 K 4 NA NA 589 0.4 47 NA 963 NA >10 K 76 NA 48NA 45 49 NA 1400 50 NA 638 NA 6607 2400 NA >10 K >10 K 3162 51 NA NA NA700 NA 52 NA  27 NA 60 72 NA 18 53 NA 1020  NA 1862 59 NA 6.4

[0155] The foregoing description details specific methods andcompositions that can be employed to practice the present invention, andrepresents the best mode contemplated. However, it is apparent for oneof ordinary skill in the art that further compounds with the desiredpharmacological properties can be prepared in an analogous manner, andthat the disclosed compounds can also be obtained from differentstarting compounds via different chemical reactions. Similarly,different pharmaceutical compositions may be prepared and used withsubstantially the same result. Thus, however detailed the foregoing mayappear in text, it should not be construed as limiting the overall scopehereof; rather, the ambit of the present invention is to be governedonly by the lawful construction of the appended claims.

What is claimed is:
 1. A method of treating ocular hypertension orglaucoma which comprises administering to an animal having ocularhypertension or glaucoma a therapeutically effective amount of acompound represented by the general Formula I:

wherein the dashed lines indicate the presence or absence of a bond, thehatched wedges indicate the α (down) configuration, and the solidtriangles indicate the β (up) configuration; B is a single, double, ortriple covalent bond; n is 0-6; X is CH₂, S or O; Y is anypharmaceutically acceptable salt of CO₂H, or CO₂R, CONR₂, NHCH₂CH₂OH,N(CH₂CH₂OH)₂, —CH₂OR, P(O)(OR)₂, CONRSO₂R, SONR₂, or

R is H, C₁₋₆ alkyl or C₂₋₆ alkenyl; R² and R³ are C₁₋₆ linear alkylwhich may be the same or different, and may be bonded to each other suchthat they form a ring incorporating the carbon to which they arecommonly attached; R⁴ is hydrogen, R, C(═O)R, or any group that iseasily removed under physiological conditions such that R⁴ iseffectively hydrogen; R⁵ is hydrogen or R; and R⁶ is i) hydrogen; ii) alinear or branched hydrocarbon containing between 1 and 8 carbon atoms,which may contain one or more double or triple bonds, or oxygen orhalogen derivatives of said hydrocarbon, wherein 1-3 carbon or hydrogenatoms may be substituted by 0 or a halogen; or iii) aryloxy,heteroaryloxy, C₃₋₈ cycloalkyloxy, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl or C₃₋₁₀heteroaryl, wherein one or more carbons is substituted with N, O, or S;and which may contain one or more substituents selected from the groupconsisting of halogen, trihalomethyl, cyano, nitro, amino, hydroxy,C₆₋₁₀ aryl, C₃₋₁₀ heteroaryl, aryloxy, heteroaryloxy, C₁₋₆ alkyl, OR,SR, and SO₂R.
 2. The method of claim 1 wherein the compound of Formula Iis not a compound of Formula II

wherein A is CO₂H or CO₂Me; D is a single, double, or triple covalentbond; E is a linear, branched, or cycloalkyl chain of 3 to 7 carbons,trifluoromethylbutyl, hydroxylalkyl, or CH₂R⁷ wherein R⁷ is phenyl,cyclopentyl, phenoxy, chlorophenoxy, propoxy, or —CH₂SCH₂CH₃; J ishydrogen, R, C(═O)R, or any group that is easily removed underphysiological conditions such that R⁴ is effectively hydrogen; and G isH or CH₃.
 3. The method of claim 2 wherein the compound of Formula I isfurther represented by Formula III

wherein Y is CO₂R, or any pharmaceutically acceptable salt of CO₂H. 4.The method of claim 3 wherein R⁶ is C₆₋₁₀ aryl or C₃₋₁₀ heteroaryl,wherein one or more carbons is substituted with N, O, or S; and whichmay contain one or more substituents selected from the group consistingof halogen, trihalomethyl, cyano, nitro, amino, hydroxy, C₁₋₆ alkyl, OR,SR, and SO₂R.
 5. The method of claim 4 wherein R is napthyl,benzofuranyl, or benzothienyl, which may contain one or moresubstituents selected from the group consisting of halogen,trihalomethyl, cyano, nitro, amino, hydroxy, C₁₋₆ alkyl, OR, SR, andSO₂R.
 6. The method of claim 5 wherein Y is CO₂H or CO₂Me.
 7. The methodof claim 6 wherein R⁶ is 3-chlorobenzothien-2-yl.
 8. The method of claim7 wherein n is
 2. 9. The method of claim 8 wherein B is a single bond.10. The method of claim 2 wherein the compound of Formula I is furtherrepresented by Formula IV

wherein Y is CO₂R, or any pharmaceutically acceptable salt of CO₂H; andR⁶ is C₆₋₁₀ aryl or C₃₋₁₀ heteroaryl, wherein one or more carbons issubstituted with N, O, or S; and which may contain one or moresubstituents selected from the group consisting of halogen,trihalomethyl, cyano, nitro, amino, hydroxy, C₁₋₆ alkyl, OR, SR, andSO₂R.
 11. The method of claim 10 wherein Y is CO₂H or CO₂Me.
 12. Themethod of claim 11 wherein R⁶ is phenyl.
 13. The method of claim 12wherein B is a double bond.
 14. The method of claim 11 wherein R⁶ isnapthyl, benzofuranyl, or benzothienyl, which may contain one or moresubstituents selected from the group consisting of halogen,trihalomethyl, cyano, nitro, amino, hydroxy, C₁₋₆ alkyl, OR, SR, andSO₂R.
 15. The method of claim 14 wherein R⁶ is 3-chlorobenzothien-2-yl.16. The method of claim 15 wherein B is a double or triple bond.
 17. Themethod of claim 1 wherein said compound is selected from the groupconsisting of(3-{(1R,4S,5S)-5-(3-chloro-benzo[b]thiophen-2-yl)-3-hydroxy-pent-1-enyl]-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentylsulfanyl}-propylsulfanyl)-aceticacid methyl ester (21, 22);(3-{(1R,4S,5S)-5-(3-chloro-benzo[b]thiophen-2-yl)-3-hydroxy-pent-1-enyl]-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentylsulfanyl}-propylsulfanyl)-aceticacid (23, 24);(Z)-7-{(1R,4S,5R)-5-[(E)-5-(3-chloro-benzo[b]thiophene-2-yl)-3-hydroxy-pent-1-enyl]-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl}-hept-5-ynoicacid methyl ester (34, 35);(Z)-7-{(1R,4S,5R)-5-[(E)-5-(3-chloro-benzo[b]thiophene-2-yl)-3-hydroxy-pent-1-enyl]-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl}-hept-5-ynoicacid (36,37);(Z)-7-{(1R,4S,5R)-5-[(E)-5-(3-chloro-benzo[b]thiophene-2-yl)-3-hydroxy-pent-1-enyl]-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl}-hept-5-enoicacid methyl ester (38,39);(Z)-7-{(1R,4S,5R)-5-[(E)-5-(3-chloro-benzo[b]thiophene-2-yl)-3-hydroxy-pent-1-enyl]-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl}-hept-5-enoicacid (40,41);7-[(1R,4S,5R)-4-Hydroxy-5-((E)-(S)-3-hydroxy-oct-1-enyl)-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-ynoicacid methyl ester (42)7-[(1R,4S,5R)-4-Hydroxy-5-((E)-(S)-3-hydroxy-oct-1-enyl)-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-ynoicacid (43)(Z)-7-[(1R,4S,5R)-4-Hydroxy-5-((E)-(S)-3-hydroxy-oct-1-enyl)-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-enoicacid (44)(Z)-7-[(1R,4S,5R)-4-Hydroxy-5-((E)-(S)-3-hydroxy-oct-1-enyl)-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-enoicacid methyl ester (45)(Z)-7-[(1R,4S,5R)-4-Hydroxy-5-((E)-3-hydroxy-4-phenyl-but-1-enyl)-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-enoicacid (46, 47)(Z)-7-[(1R,4S,5R)-4-Hydroxy-5-((E)-3-hydroxy-4-phenyl-but-1-enyl)-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-enoicacid methyl ester (48, 49)(Z)-7-[(1R,4S,5R)-4-Hydroxy-5-((E)-3-hydroxy-5-phenyl-pent-1-enyl)-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-enoicacid methyl ester (50,51)(Z)-7-[(1R,4S,5R)-4-Hydroxy-5-((E)-3-hydroxy-5-phenyl-pent-1-enyl)-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-enoicacid (52,53)(Z)-7-[(1R,4S,5R)-5-((E)-4-Benzo[b]thiophen-2-yl-3-hydroxy-but-1-enyl)-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-enoicacid (54,55)7-[(1R,4S,5R)-5-((E)-4-Benzo[b]thiophen-2-yl-3-hydroxy-but-1-enyl)-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl]-heptanoicacid (56,57)(Z)-7-[(1R,4S,5R)-5-(4-Benzo[b]thiophen-2-yl-3-hydroxy-butyl)-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-enoicacid (58,59)(Z)-7-[(1R,4S,5R)-5-((E)-4-Benzo[b]thiophen-2-yl-3-hydroxy-but-1-enyl)-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-enoicacid ethylamide (60,61)(Z)-7-[(1R,4S,5R)-5-((E)-4-Benzo[b]thiophen-2-yl-3-hydroxy-but-1-enyl)-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-enoicacid diethylamide (62,63)(Z)-7-[(1R,4S,5R)-5-((E)-4-Benzo[b]thiophen-2-yl-3-hydroxy-but-1-enyl)-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-enoicacid (2-hydroxy-ethyl)amide (64,65)(3S,4R,5R)-4-((E)-4-Benzo[b]thiophen-2-yl-3-hydroxy-but-1-enyl)-3-hydroxy-2,2-dimethyl-5-[(Z)-6-(1-H-tetrazol-5-yl)-hex-2-enyl]-cyclopentanone(66,67)
 18. A compound represented by Formula I:

wherein the dashed lines indicate the presence or absence of a bond, thehatched wedges indicate the α (down) configuration, and the solidtriangles indicate the β (up) configuration; B is a single, double, ortriple covalent bond; n is 0-6; X is CH₂, S or O; Y is anypharmaceutically acceptable salt of CO₂H, or CO₂R, CONR₂, NHCH₂CH₂OH,N(CH₂CH₂OH)₂, CH₂OR, P(O)(OR)₂, CONRSO₂R, SONR₂, or

R is H, C₁₋₆ alkyl or C₂₋₆ alkenyl; R² and R³ are C₁₋₆ linear alkylwhich may be the same or different, and may be bonded to each other suchthat they form a ring incorporating the carbon to which they arecommonly attached; R⁴ is hydrogen, R, C(═O)R, or any group that iseasily removed under physiological conditions such that R⁴ iseffectively hydrogen; R⁵ is hydrogen or R; R⁶ is i) hydrogen; ii) alinear or branched hydrocarbon containing between 1 and 8 carbon atoms,which may contain one or more double or triple bonds, or oxygen orhalogen derivatives of said hydrocarbon, wherein 1-3 carbon or hydrogenatoms may be substituted by 0 or a halogen; or iii) aryloxy,heteroaryloxy, C₃₋₈ cycloalkyloxy, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl or C₃₋₁₀heteroaryl, wherein one or more carbons is substituted with N, O, or S;and which may contain one or more substituents selected from the groupconsisting of halogen, trihalomethyl, cyano, nitro, amino, hydroxy,C₆₋₁₀ aryl, C₃₋₁₀ heteroaryl, aryloxy, heteroaryloxy, C₁₋₆ alkyl, OR,SR, and SO₂R; and the compound of Formula I is not a compound of FormulaII

wherein A is CO₂H or CO₂Me; D is a single, double, or triple covalentbond; E is a linear, branched, or cycloalkyl chain of 3 to 7 carbons,trifluoromethylbutyl, hydroxylalkyl, or CH₂R⁷ wherein R⁷ is phenyl,cyclopentyl, phenoxy, chlorophenoxy, propoxy, or —CH₂SCH₂CH₃; J ishydrogen, R, C(═O)R, or any group that is easily removed underphysiological conditions such that R⁴ is effectively hydrogen; and G isH or CH₃.
 19. The compound of claim 18 which is further represented byFormula III

wherein Y is CO₂R, or any pharmaceutically acceptable salt of CO₂H. 20.The compound of claim 19 wherein R⁶ is C₆₋₁₀ aryl or C₃₋₁₀ heteroaryl,wherein one or more carbons is substituted with N, O, or S; and whichmay contain one or more substituents selected from the group consistingof halogen, trihalomethyl, cyano, nitro, amino, hydroxy, C₁₋₆ alkyl, OR,SR, and SO₂R.
 21. The compound of claim 20 wherein R⁶ is napthyl,benzofuranyl, or benzothienyl, which may contain one or moresubstituents selected from the group consisting of halogen,trihalomethyl, cyano, nitro, amino, hydroxy, C₁₋₆ alkyl, OR, SR, andSO₂R.
 22. The compound of claim 21 wherein Y is CO₂H or CO₂Me.
 23. Thecompound of claim 22 where R⁶ is 3-chlorobenzothien-2-yl.
 24. Thecompound of claim 23 where n is
 2. 25. The compound of claim 24 where Bis a single bond.
 26. The compound of claim 18 which is furtherrepresented by Formula IV

wherein Y is CO₂R or any pharmaceutically acceptable salt of CO₂H; andR⁶ is C₆₋₁₀ aryl or C₃₋₁₀ heteroaryl, wherein one or more carbons issubstituted with N, O, or S; and which may contain one or moresubstituents selected from the group consisting of halogen,trihalomethyl, cyano, nitro, amino, hydroxy, C₁₋₆ alkyl, OR, SR, andSO₂R.
 27. The compound of claim 26 wherein Y is CO₂H or CO₂Me.
 28. Thecompound of claim 27 wherein R⁶ is phenyl.
 29. The compound of claim 28wherein B is a double bond.
 30. The compound of claim 27 wherein R⁶ isnapthyl, benzofuranyl, or benzothienyl, which may contain one or moresubstituents selected from the group consisting of halogen,trihalomethyl, cyano, nitro, amino, hydroxy, C₁₋₆ alkyl OR, SR, andSO₂R.
 31. The compound of claim 30 wherein R⁶ is3-chlorobenzothien-2-yl.
 32. The compound of claim 31 wherein B is adouble or triple bond.
 33. The compound of claim 18 which is furtherrepresented by Formula V

wherein at least one of R² and R³ is not methyl.
 34. The compound ofclaim 33 wherein R² and R³ have a total number of carbon atoms of 6 orless.
 35. The compound of claim 34 wherein R⁵ is hydrogen.
 36. Thecompound of claim 18 wherein said compound is selected from the groupconsisting of(3-{(1R,4S,5S)-5-(3-chloro-benzo[b]thiophen-2-yl)-3-hydroxy-pent-1-enyl]-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentylsulfanyl}-propylsulfanyl)-aceticacid methyl ester (21, 22);(3-{(1R,4S,5S)-5-(3-chloro-benzo[b]thiophen-2-yl)-3-hydroxy-pent-1-enyl]-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentylsulfanyl}-propylsulfanyl)-aceticacid (23, 24);(Z)-7-{(1R,4S,5R)-5-[(E)-5-(3-chloro-benzo[b]thiophene-2-yl)-3-hydroxy-pent-1-enyl]-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl}-hept-5-ynoicacid methyl ester (34, 35);(Z)-7-{(1R,4S,5R)-5-[(E)-5-(3-chloro-benzo[b]thiophene-2-yl)-3-hydroxy-pent-1-enyl]-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl}-hept-5-ynoicacid (36,37);(Z)-7-{(1R,4S,5R)-5-[(E)-5-(3-chloro-benzo[b]thiophene-2-yl)-3-hydroxy-pent-1-enyl]-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl}-hept-5-enoicacid methyl ester (38,39); (Z)-7-{(1R4S,5R)-5-[(E)-5-(3-chloro-benzo[b]thiophene-2-yl)-3-hydroxy-pent-1-enyl]-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl}-hept-5-enoicacid (40,41);(Z)-7-[(1R,4S,5R)-4-Hydroxy-5-((E)-3-hydroxy-5-phenyl-pent-1-enyl)-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-enoicacid methyl ester (50,51)(Z)-7-[(1R,4S,5R)-4-Hydroxy-5-((E)-3-hydroxy-5-phenyl-pent-1-enyl)-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-enoicacid (52,53)(Z)-7-[(1R,4S,5R)-5-((E)-4-Benzo[b]thiophen-2-yl-3-hydroxy-but-1-enyl)-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-enoicacid (54,55)7-[(1R,4S,5R)-5-((E)-4-Benzo[b]thiophen-2-yl-3-hydroxy-but-1-enyl)-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl]-heptanoicacid (56,57)(Z)-7-[(1R,4S,5R)-5-(4-Benzo[b]thiophen-2-yl-3-hydroxy-butyl)-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-enoicacid (58,59)(Z)-7-[(1R,4S,5R)-5-((E)-4-Benzo[b]thiophen-2-yl-3-hydroxy-but-1-enyl)-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-enoicacid ethylamide (60,61)(Z)-7-[(1R,4S,5R)-5-((E)-4-Benzo[b]thiophen-2-yl-3-hydroxy-but-1-enyl)-4-hydroxy-3,3-dimethyl-2-oxo-cyclopentyl]-hept-5-enoicacid diethylamide (62,63)(Z)-7-[(1R,4S,5R)-5-((E)-4-Benzo[b]thiophen-2-yl-3-hydroxy-but-1-enyl)-4-hydroxy-3,3-dimethyl-2-oxo-cyqlopentyl]-hept-5-enoicacid (2-hydroxy-ethyl)amide (64,65)(3S,4R,5R)-4-((E)-4-Benzo[b]thiophen-2-yl-3-hydroxy-but-1-enyl)-3-hydroxy-2,2-dimethyl-5-[(Z)-6-(1-H-tetrazol-5-yl)-hex-2-enyl]-cyclopentanone(66,67)
 37. An ophthalmic solution comprising a therapeuticallyeffective amount of a compound represented by the general Formula 1

wherein the dashed lines indicate the presence or absence of a bond, thehatched wedges indicate the α (down) configuration, and the solidtriangles indicate the β (up) configuration; B is a single, double, ortriple covalent bond; n is 0-6; X is CH₂, S or O; Y is anypharmaceutically acceptable salt of CO₂H, or CO₂R, CONR₂, NHCH₂CH₂OH,N(CH₂CH₂OH)₂, CH₂OR, P(O)(OR)₂, CONRSO₂R, SONR₂, or

R is H, C₁₋₆ alkyl or C₂₋₆ alkenyl; R² and R³ are C₁₋₆ linear alkylwhich may be the same or different, and may be bonded to each other suchthat they form a ring incorporating the carbon to which they arecommonly attached; R⁴ is hydrogen, R, C(═O)R, or any group that iseasily removed under physiological conditions such that R⁴ iseffectively hydrogen; R⁵ is hydrogen or R; and R⁶ is i) hydrogen; ii) alinear or branched hydrocarbon containing between 1 and 8 carbon atoms,which may contain one or more double or triple bonds, or oxygen orhalogen derivatives of said hydrocarbon, wherein 1-3 carbon or hydrogenatoms may be substituted by 0 or a halogen; or iii) aryloxy,heteroaryloxy, C₃₋₉ cycloalkyloxy, C₃₋₈, cycloalkyl, C₆₋₁₀ aryl or C₃₋₁₀heteroaryl, wherein one or more carbons is substituted with N, O, or S;and which may contain one or more substituents selected from the groupconsisting of halogen, trihalomethyl, cyano, nitro, amino, hydroxy,C₆₋₁₀ aryl, C₃₋₁₀ heteroaryl, aryloxy, heteroaryloxy, C₁₋₆ alkyl, OR,SR, and SO₂R.
 38. A pharmaceutical product, comprising a containeradapted to dispense the contents of said container in metered form; andan ophthalmic solution according to claim 37 in said container.
 39. Themethod of making compounds of Formula V

wherein part of the synthesis comprises reducing a compound of FormulaVI to a compound of Formula VII in the presence of Baker's yeast

wherein the dashed lines indicate the presence or absence of a bond, thehatched wedges indicate the α (down) configuration, and the solidtriangles indicate the β (up) configuration; B is a single, double, ortriple covalent bond; n is 0-6; X is CH₂, S or O; Y is anypharmaceutically acceptable salt of CO₂H, CO₂R, CONR₂, NHCH₂CH₂OH,N(CH₂CH₂OH)₂, CH₂OR, P(O)(OR)₂, CONRSO₂R, SONR₂, or

R is H, C₁₋₆ alkyl or C₂₋₆ alkenyl; R² and R³ are C₁₋₆ linear alkylwhich may be the same or different, and may be bonded to each other suchthat they form a ring incorporating the carbon to which they arecommonly attached; R⁵ is hydrogen or R; and R⁶ is i) hydrogen; ii) alinear or branched hydrocarbon containing between 1 and 8 carbon atoms,which may contain one or more double or triple bonds, or oxygen orhalogen derivatives of said hydrocarbon, wherein 1-3 carbon or hydrogenatoms may be substituted by 0 or a halogen; or iii) aryloxy,heteroaryloxy, C₃₋₈ cycloalkyloxy, C₃₋₈ cycloalkyl, C₆₋₁₀ aryl or C₃₋₁₀heteroaryl, wherein one or more carbons is substituted with N, O, or S;and which may contain one or more substituents selected from the groupconsisting of halogen, trihalomethyl, cyano, nitro, amino, hydroxy,C₆₋₁₀ aryl, C₃₋₁₀ heteroaryl, aryloxy, heteroaryloxy, C₁₋₆ alkyl, OR,SR, and SO₂R.
 40. The method of making compounds of Formula VIIIcomprising:

i) reacting a compound of Formula IX with a compound of Formula X in thepresence of a suitable base to form a compound of Formula XI;

ii) coupling a compound of Formula XI with a compound of Formula XII;and

iii) removing the protecting groups and separating the diastereomers toobtain the desired products; wherein the hatched wedges indicate the α(down) configuration, the solid triangles indicate the β (up)configuration, and the wavy lines indicate either the cis (Z) or trans(Z) conformation; n is 0-6; B is a single, double, or triple covalentbond; J is a protecting group that can be easily removed to form therespective hydroxide group without affecting the rest of the molecule; Ris C₁₋₆ alkyl or C₂₋₆ alkenyl; R² and R³ are C₁₋₆ linear alkyl which maybe the same or different, and may be bonded to each other such that theyform a ring incorporating the carbon to which they are commonlyattached; X is S or O; and M is a group that comprises one or more metalatoms.
 41. The method of claim 1 wherein the compound of Formula I whichis further represented by Formula XIII

wherein B represents a single or double bond; and R⁶ is napthyl,benzofuranyl, or benzothienyl, which may contain one or moresubstituents selected from the group consisting of halogen,trihalomethyl, cyano, nitro, amino, hydroxy, C₁₋₆ alkyl, OR, SR, andSO₂R.
 42. The method of claim 41 wherein R⁶ is benzothien-2-yl.
 43. Themethod of claim 42 wherein Y is any pharmaceutically acceptable salt ofCO₂H, or CO₂R, CONR₂, NHCH₂CH₂OH, N(CH₂CH₂OH)₂, or


44. The method of claim 43 wherein the dashed line indicates thepresence of a bond and B is a double bond.
 45. The method of claim 43wherein the dashed line indicates the presence of a bond and B is asingle bond.
 46. The method of claim 43 wherein the dashed lineindicates the absence of a bond and B is a double bond.
 47. The compoundof claim 18 which is further represented by Formula XIII

wherein B represents a single or double bond; and R⁶ is napthyl,benzofuranyl, or benzothienyl, which may contain one or moresubstituents selected from the group consisting of halogen,trihalomethyl, cyano, nitro, amino, hydroxy, C₁₋₆ alkyl, OR, SR, andSO₂R.
 48. The compound of claim 47 wherein R⁶ is benzothien-2-yl. 49.The compound of claim 48 wherein Y is any pharmaceutically acceptablesalt of CO₂H, or CO₂R, CONR₂, NHCH₂CH₂OH, N(CH₂CH₂OH)₂, or


50. The compound of claim 49 wherein the dashed line indicates thepresence of a bond and B is a double bond.
 51. The compound of claim 49wherein the dashed line indicates the presence of a bond and B is asingle bond.
 52. The compound of claim 49 wherein the dashed lineindicates the absence of a bond and B is a double bond.